PROJECT SUMMARY Obesity has become an epidemic in the United States, affecting more than one-third of American adults and increasing the incidence of diabetes and other comorbidities. Weight loss elicits adaptive metabolic and hormonal changes, similar to those seen in starvation, which make maintenance of a reduced body weight more challenging. These changes include a decrease in energy expenditure that is larger than what would be expected on the basis of changes in body composition alone. In rodents, it has long been established that brown adipose tissue (BAT) is the primary site of adaptive thermogenesis or the modulation of energy expenditure and heat generation during cold exposure and overfeeding. Emerging data suggest that activated BAT may influence body weight, core body temperature, energy expenditure and blood sugar and fat metabolism in humans. Capsinoids are nunpungent analogs of capsaicin that activate BAT by stimulating sensory neurons in the gastrointestinal tract. Chronic ingestion of capsinoids may stimulate the development or recruitment of new BAT from precursor stem cells within white adipose tissue depots. The primary goal of the proposed study is to determine whether chronic ingestion of capsinoids can recruit BAT in obese individuals who lack it or merely activates BAT in those who already have it. Additional goals are to 1) ascertain whether common genetic variants influence the response to capsinoids, 2) determine the metabolic effects of chronic capsinoid ingestion and BAT activation in obesity without weight loss and 3) establish whether chronic capsinoid ingestion and BAT activation improve weight loss with a low calorie diet. 42 obese male volunteers, ages 18-45, will be recruited for a randomized, double-blind, placebo-controlled trial of capsinoid supplementation. The study will consist of two phases: the first in which subjects maintain their usual diet and activity level for 8 weeks, and the second in which subjects consume a low-calorie diet for 12 weeks. Subjects will be studied before and after each phase, including measurement of BAT, core body temperature, energy expenditure at rest, after cold exposure, and after a test meal, body composition, and blood sugar and insulin levels after a test meal. BAT will be characterized using Positron Emission Tomography/Computed Tomography (PET/CT) and Magnetic Resonance Imaging (MRI) techniques. If preliminary data are confirmed, BAT recruitment and activation through chronic capsinoid supplementation may emerge as a safe method to combat the adaptive changes in energy expenditure that are seen with weight loss in obesity.